rs138081265

Variant names:

• chr19-3637462-C-A
• rs138081265
• ENST00000589578.5:c.2072G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-3637462-C-A
• chr19-3637462-C-G
• chr19-3637462-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001300849.2(PIP5K1C):​c.2072G>T​(p.Arg691Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,535,674 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00065 (10 hom.)
• Consequence: PIP5K1C NM_001300849.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.187
• Publications: 2 publications found

Genes affected

PIP5K1C (HGNC:8996): (phosphatidylinositol-4-phosphate 5-kinase type 1 gamma) This locus encodes a type I phosphatidylinositol 4-phosphate 5-kinase. The encoded protein catalyzes phosphorylation of phosphatidylinositol 4-phosphate, producing phosphatidylinositol 4,5-bisphosphate. This enzyme is found at synapses and has been found to play roles in endocytosis and cell migration. Mutations at this locus have been associated with lethal congenital contractural syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Sep 2010]

PIP5K1C Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036550164).
• BP6: Variant 19-3637462-C-A is Benign according to our data. Variant chr19-3637462-C-A is described in ClinVar as Benign. ClinVar VariationId is 3059157.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00121 (184/152284) while in subpopulation EAS AF = 0.0252 (130/5160). AF 95% confidence interval is 0.0217. There are 3 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300849.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP5K1C	NM_012398.3	MANE Select	c.1920+1422G>T		intron	N/A	NP_036530.1	O60331-1
	PIP5K1C	NM_001300849.2		c.2072G>T	p.Arg691Leu	missense	Exon 17 of 17	NP_001287778.1	O60331-3
	PIP5K1C	NM_001195733.2		c.1920+1422G>T		intron	N/A	NP_001182662.1	O60331-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIP5K1C	ENST00000589578.5	TSL:1	c.2072G>T	p.Arg691Leu	missense	Exon 17 of 17	ENSP00000466363.1	O60331-3
	PIP5K1C	ENST00000537021.1	TSL:1	c.*362G>T		3_prime_UTR	Exon 17 of 17	ENSP00000444779.1	O60331-2
	PIP5K1C	ENST00000335312.8	TSL:1 MANE Select	c.1920+1422G>T		intron	N/A	ENSP00000335333.3	O60331-1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152166 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0247

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00238 AC: 316 AN: 132824 AF XY: 0.00224

Gnomad AFR exome AF: 0.000787

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0283

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000389

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.000651 AC: 901 AN: 1383390 Hom.: 10 Cov.: 57 AF XY: 0.000620 AC XY: 423 AN XY: 682616

African (AFR) AF: 0.000190 AC: 6 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.0209 AC: 748 AN: 35726

South Asian (SAS) AF: 0.000341 AC: 27 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33622

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5696

European-Non Finnish (NFE) AF: 0.0000315 AC: 34 AN: 1078776

Other (OTH) AF: 0.00143 AC: 83 AN: 57886

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152284 Hom.: 3 Cov.: 31 AF XY: 0.00124 AC XY: 92 AN XY: 74446

African (AFR) AF: 0.00106 AC: 44 AN: 41564

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0252 AC: 130 AN: 5160

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000749 Hom.: 1

Bravo AF: 0.00152

ExAC AF: 0.000757 AC: 13

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PIP5K1C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.58
DANN	Benign	0.89
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0037	T
PhyloP100		-0.19
Polyphen		0.0	B
Vest4		0.16
MVP		0.043
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
gMVP		0.35
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138081265; hg19: chr19-3637460; COSMIC: COSV107415603;